Sensory gating is a largely automatic process by which the brain adjusts its response to stimuli. When one stimulus is presented, there is a response; however, when the first stimulus is followed by a second stimulus soon after, the response to the second stimulus is blunted. This is an adaptive mechanism to prevent over stimulation that helps the brain focus on a stimulus among a host of other distracters, and contributes to the ability to selectively allocate attention to a significant event by silencing the background. The specific features of an individual's gating processes are viewed to be plastic, and governed by genetic and developmental processes, but also by environmental changes, neurochemical and hormonal state of the CNS. Sensory gating was shown to be disturbed in schizophrenia.
Prepulse inhibition (PPI), the phenomenon by which a low-intensity prepulse stimulus attenuates the response to a subsequent startle-eliciting stimulus, is used as a measurement of the sensory gating function (Swerdlow and Geyer, 1998). Impairment of PPI has been reported in several diseases including schizophrenia (Swerdlow et al., 2006), Huntington's chorea (Swerdlow et al., 1995), obsessive-compulsive disorder (Swerdlow et al., 1993), attention deficit hyperactivity disorder (ADHD) (Ornitz et al., 1992), and Tourette's syndrome (Castellanos et al., 1996). Importantly, PPI deficits are not unique to a single form of psychopathology. Therefore, it is often used as a paradigm for assessing the modulation of early information processing and for screening pharmacological interventions.
Schizophrenia is a complex and severe brain disorder with poorly defined etiology and pathophysiology, which affects approximately 1% of the world population. Although the risk factors that correlate with the disease are mostly congenital (i.e. genetic aberrations, prenatal infections and complications of birth), the formal diagnostic symptoms and signs of schizophrenia are not typically manifested until late adolescence or early adulthood. The emergence of these pathologies at this critical period suggests a relationship between these disorders and reproductive hormones.
During late adolescence and early adulthood, the brain undergoes extensive synaptic remodeling, including reduction in dendritic arborization, axon myelination and synaptic pruning. The integrity of these processes may be crucial for maturation of a wide range of sensory and cognitive functions that are impaired in schizophrenia.
In the recent years, several studies have uncovered the critical role of GPR54, a G protein-coupled receptor sometimes named AXOR12 or SNORF11, and kisspeptin, the natural ligand for GPR54, in the control of pubertal development (de Roux et al., 2003; Seminara et al., 2003).
Agonists of the SNORF11 receptor, such as KISS-1 peptide fragments, have been characterized as cancer metastasis suppressors (Ohtaki et al, 2001) and as analgesics (WO 2003/003983). US 2002/0106766 discloses the rat AXOR12 gene sequence, methods for identifying agonists and antagonists/inhibitors and potential uses thereof. WO 2004/087622 discloses GPR54 receptor agonist and antagonist useful for the treatment of gonadotropin related diseases.
Kisspeptin, the primary translation product of the gene KiSS-1, is a G-protein coupled receptor ligand for GPR54. KiSS-1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis (Lee et al., 1996). A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.
The primary translation product of KiSS-1 is a 145 amino acid polypeptide (Kp-145). C-terminal amidated peptides of kisspeptin have been disclosed in U.S. Pat. Nos. 6,699,965 and 7,314,754: Kp-54, also known as metastin, containing 54-amino acid residues from positions 68 (Gly) to 121 (Phe) of Kp-145, and the shorter peptides Kp-10 (residues 112-121), Kp-13 (residues109-121) and Kp-14 (residues109-121). The peptides are disclosed as suppressors of tumor metastasis and as playing an important role in the placenta. Kp-10 was later found to be a physiological invasion inhibitor of primary human trophoblasts (Bilban et al., 2003). Kisspeptin was shown to elicit the release of gonadotropin, through the stimulation of gonadotropin-releasing hormone (GnRH) secretion, by direct activation of preoptic GnRH neurons. During transition from juvenile to adulthood, there is an increase in expression of KiSS-1 mRNA in the anteroventral periventricular nucleus, which is believed to regulate GnRH neurons. Furthermore kisspeptin and GPR54 are expressed in the dentate gyrus of the hippocampus and were shown to regulate synaptic plasticity and BDNF levels (Arai, 2008). Kisspeptin has been further described as an endogenous factor which is dynamically regulated by neuronal activity and may play a role in cognition and in the pathogenesis of epilepsy (Arai et al., 2009).